System and method for cleaning noisy genetic data and determining chromosome copy number

Abstract

Disclosed herein is a system and method for increasing the fidelity of measured genetic data, for making allele calls, and for determining the state of aneuploidy, in one or a small set of cells, or from fragmentary DNA, where a limited quantity of genetic data is available. Poorly or incorrectly measured base pairs, missing alleles and missing regions are reconstructed using expected similarities between the target genome and the genome of genetically related individuals. In accordance with one embodiment, incomplete genetic data from an embryonic cell are reconstructed at a plurality of loci using the more complete genetic data from a larger sample of diploid cells from one or both parents, with or without haploid genetic data from one or both parents. In another embodiment, the chromosome copy number can be determined from the measured genetic data, with or without genetic information from one or both parents.

What is claimed is: 
     
         1 . A method for preparing non-naturally occurring preparations of amplified DNA derived from a biological sample obtained from a second individual, wherein the biological sample comprises DNA from a first individual, the method comprising:
 (a) extracting cell-free DNA from the biological sample, thereby resulting in a first non-naturally occurring preparation that includes cell-free DNA from the first individual and the second individual, wherein the biological sample is a maternal blood sample, and wherein the first individual is a fetus;   (b) preparing a second non-naturally occurring preparation of amplified DNA by amplifying a plurality of target loci on the cell-free DNA extracted from the biological sample to generate amplified DNA, thereby resulting in a second non-naturally occurring preparation that includes amplification products derived from cell-free DNA from the first individual and the second individual; and   (c) sequencing the second non-naturally occurring preparation of amplified DNA using sequencing-by-synthesis to obtain genetic data of the plurality of target loci, wherein the sequencing-by-synthesis comprises clonal amplification of the amplified DNA and determination of sequences of the clonally amplified DNA.   
     
     
         2 . The method of  claim 1 , wherein the target loci are polymorphic loci. 
     
     
         3 . The method of  claim 1 , wherein the target loci are SNP loci. 
     
     
         4 . The method of  claim 1 , wherein the target loci are on a plurality of chromosomes. 
     
     
         5 . The method of  claim 1 , wherein the amplifying comprises targeted PCR. 
     
     
         6 . The method of  claim 1 , wherein the amplifying comprises targeted PCR and universal PCR. 
     
     
         7 . The method of  claim 1 , wherein the genetic data produced by sequencing is noisy and comprises allele drop out errors. 
     
     
         8 . The method of  claim 1 , further comprising normalizing the genetic data for differences in amplification and/or sequencing efficiency between the target loci. 
     
     
         9 . The method of  claim 3 , wherein the target loci comprises about 70-500 SNPs. 
     
     
         10 . The method of  claim 3 , wherein the confidence that each SNP is correctly called is at least 95%. 
     
     
         11 . The method of  claim 3 , wherein the confidence that each SNP is correctly called is at least 99%. 
     
     
         12 . The method of  claim 1 , further comprising analyzing the genetic data of the plurality of target loci, wherein analyzing comprises assigning to the first individual the most likely genetic data for DNA from the first individual based on allele frequencies in the genetic data at the plurality of target loci.